Malignant hyperthermia susceptibility (MHS) is a potentially lethal autosomal dominant disorder of skeletal muscle metabolism. Although MHS is rare it remains an important cause of death due to anesthesia. Recently, McCarthy et al. reported a preliminary subregional location for MHS to chromosome 19ql2-l3.2. In addition, MacLennan et al. suggested on the basis of linkage data that a defect in the ryanodine receptor gene (RYDR) causes this disorder. However, genetic heterogeneity has been well described in MHS. We report here extended haplotype analyses with markers in the 19ql3. 113.2 linkage groups that confirms molecular heterogeneity in this disorder. Our data demonstrate that a defect in RYDR could not be responsible for the symptoms of MHS in two unrelated families. The objectives of the current proposal (which will be examined simultaneously) are to evaluate genetic heterogeneity in MHS and evaluate the hormone sensitive lipase (LIPE) as an alternative gene candidate. LIPE is suggested as a gene candidate because it is flanked by the same genetic markers as MHS on 19q. LIPE also regulates free fatty acid (FFA) metabolism, and FFA are abnormally elevated in MHS muscle which may explain many of the observed pathophysiologic findings in this disorder. Therefore, in order to achieve our purposes, we propose (1.) to identify polymorphisms within LIPE and use them in linkage studies to evaluate it as a gene candidate. If no recombinants are identified between LIPE and the MHS phenotype we will evaluate the LIPE cDNA sequence for a defect which causes this disorder. (2.) to evaluate heterogeneity in MHS we will ascertain 50 families, identified by a proband with 2 or more affected sibs which have been phenotyped by the North American Malignant Hyperthermia Group Protocol; (3.) to create a MHS FAMILY DNA RESOURCE available to all investigators by developing immortal cell lines from each individual studied; (4.) to conduct linkage analyses between the MHS phenotype and a complete set of DNA markers on 19q and evaluate if more than one genetic locus produces this disorder and where this gene(s) maps; (5.) to evaluate linkage between the MHS phenotype and DNA polymorphisms on other chromosomes in those families where markers on 19q do not cosegregate with this disorder.